ABSTRACT With increased interest in patient-centered outcomes research and precision medicine, investigation of heterogeneity of treatment effect (HTE) in clinical trials has emerged as a key area of study. HTE is an assessment of the degree to which the impact of an intervention varies between subgroups. Evidence from trials of selenium supplementation indicates that this is a critical area for investigation of HTE. To date, three major clinical trials of the trace element selenium (Se) as a chemopreventive agent have been completed. First, in the Nutritional Prevention of Cancer (NPC) trial, participants were supplemented with 200 g of Se per day or matching placebo, and a statistically significant 58% reduction in colorectal cancer incidence among participants randomized to receive the selenium supplement was observed. Next, the results of the Selenium and Vitamin E Prostate Cancer Prevention Trial (SELECT) were published. The largest trial to date of Se for cancer prevention, SELECT demonstrated no reduction in risk of colorectal cancer among men supplemented with 200 g/d of Se as L-selenomethionine. We have recently completed the Selenium Trial, which was the third major clinical trial of Se for chemoprevention. This was a Phase III, randomized, double-blind, placebo-controlled clinical trial in which 1535 participants received 200 g/d of Se as selenized yeast or placebo to ascertain whether Se supplementation reduced the risk of colorectal adenoma recurrence. No differences in overall colorectal adenoma recurrence by intervention group were detected; however, subgroup analyses revealed the presence of heterogeneity of treatment effect (HTE). Among participants who had an advanced adenoma at baseline, there was a statistically significant reduction in adenoma recurrence for those randomized to Se as compared to placebo. However, there was also a statistically significant increase in the incidence of type 2 diabetes (T2D) among older participants (>63 years) receiving selenium. These results identify a major research gap regarding the need for identification of individual characteristics that may contribute to HTE and thus determine whether Se supplementation elicits a beneficial or harmful effect. This is a particularly timely question given that approximately half of American adults report using dietary supplements. We propose herein to investigate several factors that may affect individual outcomes related to Se supplementation, including 1) Genetic background; 2) Intake and blood concentrations of fat-soluble antioxidants; and 3) Oxylipin profiles in response to Se supplementation. In summary, we contend that the in vivo efficacy and toxicity of Se in a given individual may be influenced by genetic background, interactions with antioxidants, and oxylipin metabolomic profiles. The findings of this study will have a direct impact on public health recommendations by identifying individual characteristics that may elicit either beneficial or harmful health effects of Se supplementation.